Management of lower extremity neuropathic ulcers in diabetic patients has changed little in the past decade. The healing rate is poor, risk of amputations relatively high, and there is a paucity of objective methods for choosing treatments. We will carry out a multi-center clinical cohort study of circulating and wound margin vasculogenic stem/progenitor cells (SPCs) in diabetic patients undergoing treatment for lower extremity neuropathic ulcers. The goal is to develop simple, quantitative methods that provide guidance on effective treatment choices. Our hypothesis is that an analysis of SPCs number and their biochemical characteristics can predict whether diabetic foot ulcers will heal. The experimental approach is built on the very productive framework used in our preliminary R21 project and recent publication. The four specific aims center on SPCs and their association with traditional methods for assessing diabetic control and wound characteristics. Aims are as follows: (1) Determine whether SPCs mobilization/wound recruitment and hypoxia inducible factor-related processes are associated with wound repair, (2) Assess if wound care practices are associated with SPCs mobilization and SPCs homing to wounds, (3) Determine if variations in SPCs are associated with healing, and (4) Assess whether SPCs differences observed between a healing acute biopsy wound versus the foot ulcer are related to clinical issues such as metabolic status. We will evaluate whether SPCs number and content of several intracellular proteins correlate with wound and disease-related factors and whether these measurements can be used to predict diabetic wound healing. PUBLIC HEALTH RELEVANCE: We plan to carry out a multi-center clinical cohort study of circulating and wound margin vasculogenic stem/progenitor cells in diabetic patients undergoing treatment for limb-threatening lower extremity neuropathic ulcers. The goal is to develop simple, quantitative methods to assess ulcers that provide guidance on effective treatment choices. Our hypothesis is that an analysis of stem/progenitor cell number and their biochemical characteristics can predict whether diabetic foot ulcers will heal.